Thymoma is a rare tumor, but nevertheless is the most common neoplasm of the anterior mediastinal compartment. The overall incidence of malignant thymoma in US (1973-1998) was 0.15 per 100000 person/years (849 cases) [Source: “Malignant thymoma in the United States: demographic patterns in incidence and associations with subsequent malignancies” Int. J. Cancer, 2003; 105(4): 546-51]. Thymoma is considered to have an indolent growth, but it has a potential for local invasion, pleural dissemination and distant metastases. Patients with locally advanced or disseminated thymoma are usually symptomatic, presenting with chest pain, shortness of breath, paralysis of the phrenic nerve, pleural effusion and superior vena cava syndrome. Immune disorders have also been associated with thymoma, the most common being myasthenia gravis (Wright C. Management of thymomas. Crit. Rev. Oncol. Hematol., 2008; 65(2): 109-20). Thymic carcinomas are usually advanced at diagnosis, have a higher recurrence rate and a worse prognosis (survival) compared with other thymomas (NCI PDQ [Physician Data Query]®, last modified May 8, 2008).
TRKA seems to play a significant role in the biology of thymoma. Expression of neurotrophin receptors was indeed specifically documented in thymic epithelial tumors on a quite large series of patients (99 patients) (Kim D J, Yang W I, Kim S H, Park I K, Chung K Y. Expression of neurotrophin receptors in surgically resected thymic epithelial tumors. Eur. J. Cardiothorac. Surg., 2005; 28(4): 611-6). In this study, the pattern of TRKA expression was analyzed according to WHO classification for the histologic subtypes of thymic tumors. All tumor types (namely A, AB, B1, B2, B3, C) were found to evidence (by immunostaining) the presence of TRKA and the proportion of tumors which demonstrated intense immunoreactivity gradually increased from type A to type C. Conversely, any type of thymoma showed TRKB or TRKC immunoreactivity, thus suggesting a specific role (to be anyway further elucidated) for TRKA in this disease.
Besides the above mentioned WHO histological classification of thymoma, the Masaoka staging system is commonly employed to evaluate invasiveness and to base the therapeutic choice, since the optimal treatment for this disease depends on its clinical stage (NCI PDQ [Physician Data Query] ®, last modified May 8, 2008). Surgery (with or without radiotherapy) is the mainstay of early-stage thymoma treatment, because in most cases the disease is localized. Radiation and chemotherapy are generally widely applied as adjuvant and palliative procedures. (Kondo K. Optimal therapy for thymoma. J. Med. Invest., 2008; 55(1-2): 17-28). Advanced invasive thymomas (such as tumors with great vessel invasion, pleural and/or pericardial dissemination, lymphnode involvement or distant metastases) are not usually manageable by surgical resection or radiotherapy alone (Yokoi K, Matsuguma H, Nakahara R, Kondo T, Kamiyama Y, Mori K, et al. Multidisciplinary treatment for advanced invasive thymoma with cisplatin, doxorubicin, and methylprednisolone. J. Thorac. Oncol. 2007; 2(1): 73-8). Locally advanced or metastatic thymomas are often treated with combined treatment modalities, including radiation and chemotherapy. Thymomas are generally chemosensitive tumors. Chemotherapy was shown indeed to have significant antitumor activity against unresectable, recurrent or metastatic thymomas, producing an overall objective response in an average of two thirds of patients and complete remissions in one third. Cisplatin/doxorubicin-based combination chemotherapy [PAC regimen (cisplatin, doxorubicin, cyclophosphamide) or ADOC regimen (doxorubicin, cisplatin, vincristine, cyclophosphamide)] seem to produce the best overall response rate and survival. Other combined and/or single agent chemotherapy with cisplatin, etoposide, ifosfamide, epirubicin, maytansine and steroids are used as well (Kondo K., 2008, see above). Optimal treatment strategy has anyway not yet been determined and other drugs are warranted to improve the outcome of patients with advanced invasive tumors (Yokoi K, 2007).
There is therefore an unmet medical need for new potent agents for the treatment of thymoma and in particular of thymic carcinoma. The present invention addresses this problem.